Use of glucocorticoid receptor antagonists in combination with glucocorticoids to treat adrenal insufficiency

ABSTRACT

This invention provides for a method of treating secondary adrenal insufficiency by co-administrating therapeutically effective amounts of a glucocorticoid and a glucocorticoid receptor antagonist to the patient in need thereof. In some embodiments, the method includes the proviso that the patient not be otherwise in need of treatment with a glucocorticoid and a glucocorticoid receptor antagonist. The treatment method can increase the patient&#39;s morning or basal cortisol level to at least about 12 μg/dL or a standard control level, and in turn, expedite significantly the recovery of the HPA axis. The method provided herein can improve health outcomes and life-threatening complications associated with secondary adrenal insufficiency.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a U.S. Divisional patent application of U.S. patentapplication Ser. No. 16/816,014, filed Mar. 11, 2020, which is a U.S.Divisional patent application of U.S. patent application Ser. No.15/565,291, filed Oct. 9, 2017, (now U.S. Pat. No. 10,610,534, issuedApr. 7, 2020), which is a U.S. National Phase entry under 35 U.S.C. §371 of International Application No. PCT/US2016/024981, filed Mar. 30,2016, which claims priority to U.S. Provisional Application No.62/140,317, filed Mar. 30, 2015, the disclosures of which are herebyincorporated by reference in their entireties for all purposes.

BACKGROUND OF THE INVENTION

Adrenal insufficiency is an endocrine disorder that occurs when theadrenal glands do not produce adequate amounts of steroid hormones, suchas cortisol. Primary adrenal insufficiency occurs when the adrenalglands are either destroyed or absent. Secondary adrenal insufficiencyoccurs when the adrenal glands are intact, but are not stimulated toproduce cortisol due to the absence or low levels of adrenocorticotropichormone (ACTH).

ACTH is a polypeptide-based hormone that is normally produced andsecreted by the anterior pituitary gland. ACTH stimulates secretion ofcortisol and other glucocorticoids (GCs) by specialized cells of theadrenal cortex. In healthy mammals, ACTH secretion is tightly regulated.ACTH secretion is positively regulated by corticotropin releasinghormone (CRH), which is released by the hypothalamus. ACTH secretion isnegatively regulated by cortisol and other glucocorticoids. A disruptionto the tightly regulated hypothalamus-pituitary-adrenal gland (HPA) axiscan cause low levels of ACTH, and in turn, secondary adrenalinsufficiency.

Low ACTH secretion generally results from prolonged exposure toglucocorticoid drugs, or conditions that cause a total absence of ACTHor a suppression of ACTH production/secretion. Such conditions includepituitary tumors, craniopharyngiomas, radiation therapy to thepituitary, cysts in the pituitary, some inflammatory diseases, andsurgical removal of ACTH-secreting and cortisol-secreting tumors.Patients with pituitary ACTH-secreting tumors (Cushing's Disease) andpatient with non-pituitary ACTH- and cortisol-secreting tumors(Cushing's Syndrome) can be treated by tumor resection. Removal of thetumor is invariably followed by secondary adrenal insufficiency, and theneed for glucocorticoid replacement therapy.

The most common cause of secondary adrenal insufficiency is the use oflong-term glucocorticoid (GC) replacement therapy which is used to treatnumerous diseases and disorders. For instance, glucocorticoids, such asprednisone, cortisone, methylprednisolone, hydrocortisone, anddexamethasone, are recommending for treating rheumatoid arthritis,systemic lupus erythematosus, Sjögren's syndrome, ulcerative colitis,inflammatory bowel disease, chronic obstructive pulmonary disease,psoriasis, systemic vasculitis, myositis, asthma, allergic rhinitis,other allergies, skin conditions, inflammatory diseases, etc. Syntheticglucocorticoids are steroid hormones that mimic the function ofcortisol, and thus reduce endogenous cortisol levels. The pituitaryrecognizes glucocorticoids as cortisol, and thus produces lower levelsof ACTH. ACTH suppression, in turn, reduces endogenous cortisolproduction/secretion. When glucocorticoids are withdrawn and the HPAaxis fails to produce adequate levels of ACTH, secondary adrenalinsufficiency can occur. Adrenal insufficiency originates from thesuppression of the hypothalamic CRH producing cells by chronicglucocorticoid excess which consequently impairs pituitary-adrenalfunction. In addition, glucocorticoids inhibit the secretion of storedACTH and repress the transcription of the POMC gene, which encodes thepeptide ACTH. In exogenous Cushing's syndrome, the length and dose ofglucocorticoid exposure are independent predictors of recovery ofadrenal function.

Secondary adrenal insufficiency is currently treated with glucocorticoiddrugs to substitute for cortisol until the HPA axis recovers to restoreACTH and cortisol to normal levels. The time-limiting step for HPArecovery appears to be the CRH producing neurons of the hypothalamus.Unfortunately, glucocorticoid replacement therapy can prolong therecovery of the HPA axis when a high dose is used or if the timing of GCadministration is inappropriate (e.g., when it is given every 8 or 12hours). The main risk for patients with secondary adrenal insufficiencyis poor response to GC therapy. As such, novel and efficaciouspharmacotherapies that are needed to promote recovery of the HPA axis inpatients with secondary adrenal insufficiency.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention provides a method for treating apatient suspected of having secondary adrenal insufficiency. In someembodiments, the patient has secondary adrenal insufficiency. The methodcomprises co-administering a therapeutically effective amount of aglucocorticoid (GC) and a glucocorticoid receptor antagonist (GRA) to apatient in need thereof to increase the patient's morning plasma levelof cortisol to at least about 12 μg/dL or a standard control level. Insome cases, the patient's morning plasma level of cortisol increased toabout 12 μg/dL, about 13 μg/dL, about 14 μg/dL, about 15 μg/dL, about 16μg/dL, about 17 μg/dL, about 18 μg/dL, about 19 μg/dL, about 20 μg/dL,about 21 μg/dL, about 22 μg/dL, about 23 μg/dL, about 24 μg/dL, about 25μg/dL, or more. In some embodiments, if the patient suffering fromsecondary insufficiency has a cortisol level below 12 μg/dL, e.g., fromabout 5 μg/dL to about 11.9 μg/dL, administration of GC and GRA canincrease the patient's cortisol level to about 18 μg/dL or more, e.g.,18 μg/dL, about 19 μg/dL, about 20 μg/dL, about 21 μg/dL, about 22μg/dL, about 23 μg/dL, about 24 μg/dL, about 25 μg/dL, or more, afterACTH administration (Cosyntropin stimulation test). In some embodiments,the subject is not otherwise in need of a combination treatment with aglucocorticoid and glucocorticoid receptor antagonist.

In some embodiments, the patient is suspected of having secondaryadrenal insufficiency due to exogenous Cushing's syndrome (e.g., due toprolonged use of a glucocorticoid). In other embodiments, the patient issuspected of having secondary adrenal insufficiency after surgery forendogenous Cushing's syndrome. In some cases, the patient is suspectedof having secondary adrenal insufficiency after successful surgery of apituitary ACTH secreting tumor. In other cases, the patient is suspectedof having secondary adrenal insufficiency after successful surgery foran extra-adrenal cortisol secreting tumor (e.g., ovarian cancer). Insome cases, the patient is suspected of having secondary adrenalinsufficiency after successful surgery for a unilateral hyperplasticadrenal gland associated with autonomous cortisol secretion. Forexample, the patient can have secondary adrenal insufficiency aftersuccessful surgery for an ectopic ACTH secreting non pituitary tumor. Inanother case, the patient can have secondary adrenal insufficiency aftersuccessful surgery for a unilateral adrenocortical cortisol secretingtumor.

In some embodiments, the patient has not received glucocorticoids andglucocorticoid receptor antagonist treatment (e.g., GCs or GRAs incombination with GCs). In some instances, the patient has not receivedglucocorticoids and glucocorticoid receptor antagonist treatment (e.g.,GCs or GRAs in combination with GCs) to treat a disorder or conditionselected from the group consisting of glaucoma, inflammatory diseases,rheumatoid arthritis, asthma and rhinitis, chronic pulmonary disease,allergies, and autoimmune diseases. In some cases the patient has notreceived glucocorticoids and glucocorticoid receptor antagonisttreatment (e.g., GCs or GRAs in combination with GCs) to reduce a sideeffect of glucocorticoid treatment. For instance, the side effect can beweight gain, glaucoma, fluid retention, increased blood pressure, moodswings, cataracts, high blood sugar, diabetes, infection, loss ofcalcium from bones, osteoporosis, menstrual irregularities, fatredistribution, growth retardation, cushingoid appearance, or anycombination thereof.

In some cases, the glucocorticoid receptor antagonist is a selectiveinhibitor of the glucocorticoid receptor. In some embodiments, theglucocorticoid receptor antagonist comprises a steroidal backbone withat least one phenyl-containing moiety in the 11-β position of thesteroidal backbone. In some cases, the phenyl-containing moiety in the11-β position of the steroidal backbone is a dimethylaminophenyl moiety.In some cases, the glucocorticoid receptor antagonist is mifepristone.In some embodiments, the glucocorticoid receptor antagonist is selectedfrom the group consisting of11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9estradien-3-one and(17α)-17-hydroxy-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one. In someembodiments, the glucocorticoid receptor antagonist is(11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

In some embodiments, the glucocorticoid receptor antagonist has anon-steroidal backbone. In some cases, the glucocorticoid receptorantagonist backbone is a cyclohexyl pyrimidine. In some cases, whereinthe cyclohexyl pyrimidine has the following formula:

wherein the dashed line is absent or a bond; X is selected from thegroup consisting of O and S; R¹ is selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionallysubstituted with from 1 to 3 R^(1a) groups; each R^(1a) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkyl OR^(1b), halogen, C₁₋₆ haloalkyl, C₁₋₆haloaloxy, OR^(1b), NR^(1b)R^(1c), C(O)R^(1b), C(O)OR^(1b), OC(O)R^(1b),C(O)NR^(1b)R^(1c), NR^(1b)C(O)R^(1c), SO₂R^(1b), SO₂NR^(1b)R^(1c),cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R^(1b) and R^(1c) areeach independently selected from the group consisting of H and C₁₋₆alkyl; R² is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkyl-OR^(1b), C₁₋₆ alkyl NR^(1b)R^(1c) and C₁₋₆ alkyleneheterocycloalkyl; R³ is selected from the group consisting of H and C₁₋₆alkyl; Ar is aryl, optionally substituted with 1-4 R⁴ groups; each R⁴ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, C₁₋₆ haloalkyl and C₁₋₆ haloalkoxy; L¹ is a bond orC₁₋₆ alkylene; and subscript n is an integer from 0 to 3, or salts andisomers thereof.

In some cases, the glucocorticoid receptor antagonist backbone is afused azadecalin. In some cases, the fused azadecalin is a compoundhaving the following formula:

wherein L¹ and L² are members independently selected from a bond andunsubstituted alkylene; R¹ is a member selected from unsubstitutedalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl,—OR^(1A) NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D) and —C(O)OR^(1A), whereinR^(1A) is a member selected from hydrogen, unsubstituted alkyl andunsubstituted heteroalkyl, R^(1C) and R^(1D) are members independentlyselected from unsubstituted alkyl and unsubstituted heteroalkyl, whereinR^(1C) and R^(1D) are optionally joined to form an unsubstituted ringwith the nitrogen to which they are attached, wherein said ringoptionally comprises an additional ring nitrogen; R² has the formula:

wherein R^(2G) is a member selected from hydrogen, halogen,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃; J is phenyl;t is an integer from 0 to 5; X is —S(O₂)—; and R⁵ is phenyl optionallysubstituted with 1-5 R^(5A) groups, wherein R^(5A) is a member selectedfrom hydrogen, halogen, —OR^(5A1), S(O₂)NR^(5A2)R^(5A3), —CN, andunsubstituted alkyl, wherein R^(5A1) is a member selected from hydrogenand unsubstituted alkyl, and R^(5A2) and R^(5A3) are membersindependently selected from hydrogen and unsubstituted alkyl, or saltsand isomers thereof.

In some cases, the glucocorticoid receptor antagonist backbone is aheteroaryl ketone fused azadecalin or an octahydro fused azadecalin. Insome cases, the heteroaryl ketone fused azadecalin has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl; ring J is selected from the group consisting of acycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroarylring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6ring members and from 1 to 4 heteroatoms each independently selectedfrom the group consisting of N, O and S; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₆ haloalkyl, C₁ ₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, CN,OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a), C(O)NR^(2a)R^(2b), SR^(2a),S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl,wherein the heterocycloalkyl groups are optionally substituted with 1-4R^(2c) groups; alternatively, two R² groups linked to the same carbonare combined to form an oxo group (═O); alternatively, two R² groups arecombined to form a heterocycloalkyl ring having from 5 to 6 ring membersand from 1 to 3 heteroatoms each independently selected from the groupconsisting of N, O and S, wherein the heterocycloalkyl ring isoptionally substituted with from 1 to 3 R^(2d) groups; R^(2a) and R^(2b)are each independently selected from the group consisting of hydrogenand C₁₋₆ alkyl; each R^(2c) is independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,CN, and NR^(2a)R^(2b); each R^(2d) is independently selected from thegroup consisting of hydrogen and C₁₋₆ alkyl, or two R^(2d) groupsattached to the same ring atom are combined to form (═O); R³ is selectedfrom the group consisting of phenyl and pyridyl, each optionallysubstituted with 1-4 R^(3a) groups; each R^(3a) is independentlyselected from the group consisting of hydrogen, halogen, and C₁₋₆haloalkyl; and subscript n is an integer from 0 to 3; or salts andisomers thereof.

In some cases, the octahydro fused azadecalin has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of an aryl ring and a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms eachindependently selected from the group consisting of N, O and S; each R²is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a),C(O)NR^(2a)R^(2b), SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl,and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S;alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(2c) groups; R^(2a), R^(2b) and R^(2c) are eachindependently selected from the group consisting of hydrogen and C₁₋₆alkyl; each R^(3a) is independently halogen; and subscript n is aninteger from 0 to 3, or salts and isomers thereof.

In some embodiments, the glucocorticoid is selected from the groupconsisting of hydrocortisone, prednisone, dexamethasone, aglucocorticoid analogue, a synthetic glucocorticoid analogue, aglucocorticoid receptor agonist, and derivatives thereof.

In some embodiments, the patient has been administered an exogenousglucocorticoid for a long period of time. In some cases, the long periodof time is at least three weeks, e.g., 3 weeks, 4 weeks, 1 month, 2months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, 1.5 years, 2 years, 3 years ormore. In some cases, the exogenous glucocorticoid is prednisone,prednisolone, hydrocortisone, dexamethasone, or a combination thereof.

Other objects, features, and advantages of the present invention will beapparent to one of skill in the art from the following detaileddescription and figures.

DETAILED DESCRIPTION OF THE INVENTION I. Introduction

The invention provides a novel treatment method for treating secondaryadrenal insufficiency in a subject in need thereof by administeringtherapeutically effective amounts of a glucocorticoid receptorantagonist (GRA) and a glucocorticoid (GC). Administration of thiscombination treatment can promote the production and/or secretion ofcortisol such that the subject's morning cortisol level in plasma is atleast about 12 μg/dL or a standard control level. In some embodiments,the method includes the proviso that the patient is not otherwise inneed of administration with a GC and GRA for treatment of glaucoma,inflammatory diseases, rheumatoid arthritis, asthma and rhinitis,chronic obstructive pulmonary disease, allergies and autoimmunediseases. In some embodiments, the method also includes the proviso thatthe patient is not otherwise in need of combination treatment with a GCand GRA for the reduction of a side effect of GC monotreatment, such asweight gain, glaucoma, fluid retention, increased blood pressure, moodswings, cataracts, high blood sugar, diabetes, infection, loss ofcalcium from bones, osteoporosis, menstrual irregularities, fatredistribution, growth retardation and cushingoid appearance.

II. Definitions

As used herein, the following terms have the meanings ascribed to themunless specified otherwise. The abbreviations used herein have theirconventional meaning within the chemical and biological arts.

The term “secondary adrenal insufficiency” refers to a condition inwhich the adrenal glands do not produce adequate amounts of cortisol dueto a lack of adrenocorticotrophic hormone (ACTH). Unlike patients withprimary adrenal insufficiency, those with secondary adrenalinsufficiency produce substantially normal levels of aldosterone andhave at least one intact adrenal gland. Secondary adrenal insufficiencyis common in patients given long-term glucocorticoid-replacementtherapy.

The term “Cushing's syndrome” refers to a disease caused by prolongedexposure to endogenous or exogenous glucocorticoids. Symptoms ofCushing's syndrome include, but are not limited to one or more of thefollowing: weight gain, high blood pressure, poor short term memory,poor concentration, irritability, excess hair growth, impairedimmunological function, ruddy complexion, extra fat in the neck region,moon face, fatigue, red stretch marks, irregular menstruation, or acombination thereof. Symptoms of Cushing's syndrome can additionally oralternatively include without limitation one or more of the following:insomnia, recurrent infection, thin skin, easy bruising, weak bones,acne, balding, depression, hip or shoulder weakness, swelling of theextremities, diabetes mellitus, elevated white blood cell count,hypokalemic metabolic alkalosis, or a combination thereof.

The term “endogenous Cushing's syndrome” refers to a type of Cushing'ssyndrome caused by, for example, endogenous overproduction of cortisolby a pituitary ACTH-secreting tumor (Cushing's disease), a non-pituitaryACTH-secreting tumor, or a cortisol-secreting tumor (adrenal orextra-adrenal). An ACTH-secreting tumor can be pituitary adenomas,pituitary adenocarcinomas, carincinoid tumors and neuroendocrine tumorsCortisol-secreting tumors include, and are not limited to, cortisolproducing adrenal adenomas, adrenocortical carcinomas, primary pigmentedmicronodular adrenal disease (PPNAD), ACTH independent macronodularadrenal hyperplasia (AIMAH), and extra-adrenal cortisol secretingtumors, e.g., ovarian carcinomas.

The term “exogenous Cushing's syndrome” refers to a type of Cushing'ssyndrome caused by repeated or prolonged administration of syntheticglucocorticoids, such as prednisone, hydrocortisone, dexamethasone andthe like. Subjects receiving long-term steroid replacement therapy,exhibiting symptoms or signs of Cushing's syndrome, and having low serumcortisol levels may have exogenous Cushing's syndrome. A standardreference range for low serum cortisol level is <about 4 μg/dL in themorning.

“Treat,” “treating” and “treatment” refer to any indicia of success inthe treatment or amelioration of a pathology or condition, including anyobjective or subjective parameter such as abatement; remission;diminishing of symptoms or making the pathology or condition moretolerable to the patient; slowing in the rate of degeneration ordecline; making the final point of degeneration less debilitating; orimproving a patient's physical or mental well-being. The treatment oramelioration of symptoms can be based on objective or subjectiveparameters; including the results of a physical examination;histopathological examination (e.g., analysis of biopsied tissue);laboratory analysis of urine, saliva, an inferior petrosal sinus sample,serum, plasma, or blood (e.g., to detect cortisol or adrenocorticotropichormone levels); or imaging (e.g., imaging of detectably labeledoctreotide). Effective treatment can refer to an increase in cortisoland/or adrenocorticotropic hormone in a subject's body.

“Patient” or “subject in need thereof” refers to a person having, orsuspected of having, a secondary adrenal insufficiency.

As used herein, the term “simultaneously administering or sequentiallyadministering” or “coadministering”, as used interchangeably, refers toadministration of a GRA compound and glucocorticoid (GC) such that thetwo compounds are in the body at the same time in amounts effective totreat a secondary adrenal insufficiency.

As used herein, the term “effective amount,” “amounts effective,” or“therapeutically effective amount” refers to an amount or amounts of oneor more pharmacological agents effective to treat, eliminate, ormitigate at least one symptom of the disease being treated. In somecases, “effective amount,” “amounts effective,” or “therapeuticallyeffective amount” can refer to an amount of a functional agent or of apharmaceutical composition useful for exhibiting a detectabletherapeutic or inhibitory effect. The effect can be detected by anyassay method known in the art. In some cases, the amounts effective, orthe like, refer to amounts effective to increase ACTH levels or cortisol(e.g., plasma cortisol, serum cortisol, salivary cortisol, or urinaryfree cortisol) levels. In some cases, the amounts effective, or thelike, refer to amounts effective to increase ACTH levels or cortisollevels, or a combination thereof, by at least 10%, 20%, 30%, 40%, 50%,60%, 75%, 90%, 99%, or more.

The term “morning plasma level of cortisol” refers to a level, amount orconcentration of cortisol in plasma in the morning, e.g., between about7 a.m. to about 9 a.m. To measure a patient's morning plasma level ofcortisol, samples are drawn from the patient with normal circadianrhythms (e.g., a nighttime sleep cycle) between 7 a.m. and 9 a.m. Thenormal range of serum cortisol in the morning is about 4 μg/dL to about28 μg/dL. To convert from μg/dL cortisol to nmol/L cortisol, multiply bythe cortisol conversion factor (27.59).

The term “standard control level,” in the context of a plasma cortisollevel, refers to a level, amount or concentration of cortisol asdetermined in a control individual, such as a healthy individual, anindividual who does not have secondary adrenal insufficiency. In someinstances, a standard control level is an average standard control leveldetermined from a control population of individuals, e.g., a populationof healthy, normal individuals. In some embodiments, these individualsare within the appropriate parameters, if applicable, for the purpose ofscreening for and/or monitoring for secondary adrenal insufficiencyusing the methods of the present disclosure. Optionally, the individualsare of similar age or similar ethnic background. The status of theselected individuals can be confirmed by well established, routinelyemployed methods including but not limited to general physicalexamination of the individuals and general review of their medicalhistory.

The phrase “prolonged use of a glucocorticoid” refers to theadministration of one glucocorticoid drug to a patient for the treatmentof a disease or disorder wherein the patient receives the glucocorticoiddrug for a period of time, for example, at least three weeks or more. Insome cases, the patient receives a high dose of glucocorticoid drug andundergoes drug tapering (gradual withdrawl or discontinuation of thedrug) before the drug treatment is stopped.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors and colors, and the like. One of skill in the art will recognizethat other pharmaceutical excipients are useful in the presentinvention.

“Glucocorticoid” (“GC”) refers to a steroid hormone that binds to aglucocorticoid receptor. Glucocorticoids are typically characterized byhaving 21 carbon atoms, an α,β-unsaturated ketone in ring A, and anα-ketol group attached to ring D. They differ in the extent ofoxygenation or hydroxylation at C-11, C-17 and C-19 (Rawn, “Biosynthesisand Transport of Membrane Lipids and Formation of CholesterolDerivatives,” in Biochemistry, Daisy et al. (eds.), 1989, pg. 567). Theterm “glucocorticoid” includes any compound known in the art that isreferred to as a glucocorticoid receptor agonist, glucocorticoid,glucocorticosteroid, corticoid, corticosteroid, or steroid that binds toand activates a glucocorticoid receptor.

“Glucocorticoid receptor” (“GR”) refers to the type II GR whichspecifically binds to cortisol and/or cortisol analogs such asdexamethasone (See, e.g., Turner & Muller, J Mol Endocrinol, 2005 35283-292). The GR is also referred to as the cortisol receptor. The termincludes isoforms of GR, recombinant GR and mutated GR. Inhibitionconstants (K_(i)) against the human GR receptor type II (Genbank:P04150) are between 0.0001 nM to 1,000 nM; preferably between 0.0005 nMto 10 nM, and most preferably between 0.001 nM to 1 nM.

The term “glucocorticoid receptor antagonist” or “GRA” refers to anycomposition or compound which partially or completely inhibits(antagonizes) the binding of a glucocorticoid receptor (GR) agonist,such as cortisol, or cortisol analogs, synthetic or natural, to a GR. A“specific glucocorticoid receptor antagonist” refers to any compositionor compound which inhibits any biological response associated with thebinding of a GR to an agonist. By “specific,” the drug preferentiallybinds to the GR rather than other nuclear receptors, such asmineralocorticoid receptor (MR), androgen receptor (AR), or progesteronereceptor (PR). It is preferred that the specific glucocorticoid receptorantagonist bind GR with an affinity that is 10× greater ( 1/10^(th) theK_(d) value) than its affinity to the MR, AR, or PR, both the MR and PR,both the MR and AR, both the AR and PR, or to the MR, AR, and PR. In amore preferred embodiment, the specific glucocorticoid receptorantagonist binds GR with an affinity that is 100× greater ( 1/100^(th)the K_(d) value) than its affinity to the MR, AR, or PR, both the MR andPR, both the MR and AR, both the AR and PR, or to the MR, AR, and PR.

The term “selective inhibitor” in the context of glucocorticoidreceptor, refers to a chemical compound that selectively interferes withthe binding a specific glucocorticoid receptor agonist and aglucocorticoid receptor.

The term “steroidal backbone” in the context of glucocorticoid receptorantagonists containing such refers to glucocorticoid receptorantagonists that contain modifications of the basic structure ofcortisol, an endogenous steroidal glucocorticoid receptor ligand. Thebasic structure of a steroidal backbone is provided as Formula I:

The two most commonly known classes of structural modifications of thecortisol steroid backbone to create glucocorticoid antagonists includemodifications of the 11-β hydroxy group and modification of the 17-βside chain (See, e. g., Lefebvre (1989) J. Steroid Biochem. 33:557-563).

As used herein, the phrase “non-steroidal backbone” in the context ofglucocorticoid receptor antagonists containing such refers toglucocorticoid receptor antagonists that do not share structuralhomology to, or are not modifications of, cortisol. Such compoundsinclude synthetic mimetics and analogs of proteins, including partiallypeptidic, pseudopeptidic and non-peptidic molecular entities.

Non-steroidal GRA compounds also include glucocorticoid receptorantagonists having a cyclohexyl-pyrimidine backbone, a fused azadecalinbackbone, a heteroaryl ketone fused azadecalin backbone, or an octahydrofused azadecalin backbone. Exemplary glucocorticoid receptor antagonistshaving a cyclohexyl-pyrimidine backbone include those described in U.S.Pat. No. 8,685,973. Exemplary glucocorticoid receptor antagonists havinga fused azadecalin backbone include those described in U.S. Pat. Nos.7,928,237; and 8,461,172. Exemplary glucocorticoid receptor antagonistshaving a heteroaryl ketone fused azadecalin backbone include thosedescribed in U.S. 2014/0038926. Exemplary glucocorticoid receptorantagonists having an octohydro fused azadecalin backbone include thosedescribed in U.S. Provisional Patent Appl. No. 61/908,333, entitledOctahydro Fused Azadecalin Glucocorticoid Receptor Modulators, AttorneyDocket No. 85178-887884 (007800US), filed on Nov. 25, 2013.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Alkyl” refers to a straight or branched, saturated, aliphatic radicalhaving the number of carbon atoms indicated. Alkyl can include anynumber of carbons, such as C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈,C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ andC₅₋₆. For example, C₁₋₆ alkyl includes, but is not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, etc.

“Alkoxy” refers to an alkyl group having an oxygen atom that connectsthe alkyl group to the point of attachment: alkyl-O—. As for the alkylgroup, alkoxy groups can have any suitable number of carbon atoms, suchas C₁₋₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentoxy, hexoxy, etc.

“Halogen” refers to fluorine, chlorine, bromine and iodine.

“Haloalkyl” refers to alkyl, as defined above, where some or all of thehydrogen atoms are replaced with halogen atoms. As for the alkyl group,haloalkyl groups can have any suitable number of carbon atoms, such asC₁₋₆. For example, haloalkyl includes trifluoromethyl, fluoromethyl,etc. In some instances, the term “perfluoro” can be used to define acompound or radical where all the hydrogens are replaced with fluorine.For example, perfluoromethane includes 1,1,1-trifluoromethyl.

“Haloalkoxy” refers to an alkoxy group where some or all of the hydrogenatoms are substituted with halogen atoms. As for the alkyl group,haloalkoxy groups can have any suitable number of carbon atoms, such asC₁₋₆. The alkoxy groups can be substituted with 1, 2, 3, or morehalogens. When all the hydrogens are replaced with a halogen, forexample by fluorine, the compounds are per-substituted, for example,perfluorinated. Haloalkoxy includes, but is not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, etc.

“Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing from 3 to12 ring atoms, or the number of atoms indicated. Cycloalkyl can includeany number of carbons, such as C₃₋₆, C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈, C₅₋₈, C₆₋₈,C₃₋₉, C₃₋₁₀, C₃₋₁₁, and C₃₋₁₂. Saturated monocyclic cycloalkyl ringsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl ringsinclude, for example, norbornane, [2.2.2] bicyclooctane,decahydronaphthalene and adamantane. Cycloalkyl groups can also bepartially unsaturated, having one or more double or triple bonds in thering. Representative cycloalkyl groups that are partially unsaturatedinclude, but are not limited to, cyclobutene, cyclopentene, cyclohexene,cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene,cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene,and norbornadiene. When cycloalkyl is a saturated monocyclic C₃₋₈cycloalkyl, exemplary groups include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. When cycloalkyl is a saturated monocyclic C₃₋₆ cycloalkyl,exemplary groups include, but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloalkyl” refers to a saturated ring system having from 3 to 12ring members and from 1 to 4 heteroatoms of N, O and S. Additionalheteroatoms can also be useful, including, but not limited to, B, Al, Siand P. The heteroatoms can also be oxidized, such as, but not limitedto, —S(O)— and —S(O)₂—. Heterocycloalkyl groups can include any numberof ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8,6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitablenumber of heteroatoms can be included in the heterocycloalkyl groups,such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3to 4. The heterocycloalkyl group can include groups such as aziridine,azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine,pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers),oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane,thiirane, thietane, thiolane (tetrahydrothiophene), thiane(tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine,isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine,dioxane, or dithiane. The heterocycloalkyl groups can also be fused toaromatic or non-aromatic ring systems to form members including, but notlimited to, indoline.

When heterocycloalkyl includes 3 to 8 ring members and 1 to 3heteroatoms, representative members include, but are not limited to,pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene,thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, morpholine,thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form aring having 5 to 6 ring members and 1 to 2 heteroatoms, withrepresentative members including, but not limited to, pyrrolidine,piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine,imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, and morpholine.

“Aryl” refers to an aromatic ring system having any suitable number ofring atoms and any suitable number of rings. Aryl groups can include anysuitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14,15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ringmembers. Aryl groups can be monocyclic, fused to form bicyclic ortricyclic groups, or linked by a bond to form a biaryl group.Representative aryl groups include phenyl, naphthyl and biphenyl. Otheraryl groups include benzyl, having a methylene linking group. Some arylgroups have from 6 to 12 ring members, such as phenyl, naphthyl orbiphenyl. Other aryl groups have from 6 to 10 ring members, such asphenyl or naphthyl. Some other aryl groups have 6 ring members, such asphenyl. Aryl groups can be substituted or unsubstituted.

“Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclicaromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5of the ring atoms are a heteroatom such as N, O or S. Additionalheteroatoms can also be useful, including, but not limited to, B, Al, Siand P. The heteroatoms can also be oxidized, such as, but not limitedto, N-oxide, —S(O)— and —S(O)₂—. Heteroaryl groups can include anynumber of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Anysuitable number of heteroatoms can be included in the heteroaryl groups,such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring membersand from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.The heteroaryl group can include groups such as pyrrole, pyridine,imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroarylgroups can also be fused to aromatic ring systems, such as a phenylring, to form members including, but not limited to, benzopyrroles suchas indole and isoindole, benzopyridines such as quinoline andisoquinoline, benzopyrazine (quinoxaline), benzopyrimidine(quinazoline), benzopyridazines such as phthalazine and cinnoline,benzothiophene, and benzofuran. Other heteroaryl groups includeheteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groupscan be substituted or unsubstituted.

The heteroaryl groups can be linked via any position on the ring. Forexample, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3-and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazoleincludes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes2-, 4-, 5- and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine,1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-,5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiopheneincludes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazoleincludes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and5-isothiazole, oxazole includes 2-, 4- and 5-oxazole, isoxazole includes3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindoleincludes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline,isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2-and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline,benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes2- and 3-benzofuran.

Some heteroaryl groups include those having from 5 to 10 ring membersand from 1 to 3 ring atoms including N, O or S, such as pyrrole,pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, and benzofuran. Other heteroaryl groupsinclude those having from 5 to 8 ring members and from 1 to 3heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-and1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, andisoxazole. Some other heteroaryl groups include those having from 9 to12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, benzofuran and bipyridine. Still otherheteroaryl groups include those having from 5 to 6 ring members and from1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine,imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan,thiazole, isothiazole, oxazole, and isoxazole.

Some heteroaryl groups include from 5 to 10 ring members and onlynitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline,quinazoline, phthalazine, and cinnoline. Other heteroaryl groups includefrom 5 to 10 ring members and only oxygen heteroatoms, such as furan andbenzofuran. Some other heteroaryl groups include from 5 to 10 ringmembers and only sulfur heteroatoms, such as thiophene andbenzothiophene. Still other heteroaryl groups include from 5 to 10 ringmembers and at least two heteroatoms, such as imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline,quinazoline, phthalazine, and cinnoline.

“Heteroatoms” refers to O, S or N.

“Salt” refers to acid or base salts of the compounds used in the methodsof the present invention. Illustrative examples of pharmaceuticallyacceptable salts are mineral acid (hydrochloric acid, hydrobromic acid,phosphoric acid, and the like) salts, organic acid (acetic acid,propionic acid, glutamic acid, citric acid and the like) salts,quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.It is understood that the pharmaceutically acceptable salts arenon-toxic. Additional information on suitable pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., 1985, which isincorporated herein by reference.

“Isomers” refers to compounds with the same chemical formula but whichare structurally distinguishable.

“Tautomer” refers to one of two or more structural isomers which existin equilibrium and which are readily converted from one form to another.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, or physiological conditions.

III. Detailed Description of Embodiments

The present invention provides a method of treating secondary adrenalinsufficiency in a subject in need thereof. In one aspect, a subjectsuffering from secondary adrenal insufficiency is administeredsimultaneously or sequentially therapeutically effective amounts of a GCand a GRA, such that the subject's plasma cortisol level in the morning(i.e., anytime from 7 a.m. to 9 a.m.) increases at least 12 μg/dL, e.g.,12 μg/dL, 13 μg/dL, 14 μg/dL, 15 μg/dL, 16 μg/dL, 17 μg/dL, 18 μg/dL, 19μg/dL, 20 μg/dL, 21 μg/dL, 22 μg/dL, or more. In some instances, thesubject has undergone treatment for endogenous Cushing's syndrome. Inother instances, the subject has exogenous Cushing's syndrome. Inanother case, the subject has been administered an exogenousglucocorticoid for a long period of time.

A. Subjects with Secondary Adrenal Insufficiency

Secondary adrenal insufficiency involves ACTH deficiency which may bedue to an abnormally functioning or damaged pituitary gland orhypothalamus. ACTH deficiency leads to insufficient cortisol production.Unlike in primary adrenal insufficiency, the adrenal glands in patientswith secondary adrenal insufficiency are intact and produce normalamounts of aldosterone. Symptoms of secondary adrenal insufficiencyinclude dizziness, fatigue, muscle weakness, weight loss, decreased orloss of appetite, nausea, vomiting, diarrhea, depression, irritability,muscle, joint, abdominal or back pain, loss of hair, headache andsweating.

Secondary adrenal insufficiency can occur in patients receiving apro-longed glucocorticoid therapy, such as synthetic glucocorticoid(e.g., prednisone, hydrocortisone, dexamethasone, cortisone) therapy.This condition is referred to as exogenous Cushing's syndrome. Whenreceiving glucocorticoids for a long time (e.g., at least three weeks ormore), the patient's adrenal glands may produce low or undetectablelevels of cortisol. Patients with exogenous Cushing's syndrome can havelow ACTH levels, low cortisol levels, and no response to a low dose ACTHstimulation test. Treatment of exogenous Cushing's syndrome includesslowly withdrawing the glucocorticoid to reverse the effects of theimpaired adrenal gland. The method described herein can promote oraccelerate the repair of the patient's HPA axis such that the adrenalglands secrete cortisol at normal, healthy levels.

Secondary adrenal insufficiency can also arise in patients withendogenous Cushing's syndrome after surgical removal of anACTH-secreting tumor or a cortisol-secreting tumor in, for example, anadrenal gland. Endogenous Cushing's syndrome is caused by ACTH-secretingtumors or cortisol-secreting tumors, e.g., cortisol producing adrenaladenomas, adrenocortical carcinomas, primary pigmented micronodularadrenal disease (PPNAD), ACTH independent macronodular adrenalhyperplasia (AIMAH), extraadrenal cortisol secreting tumors, e.g.,ovarian carcinomas, adrenal adenomas, micronodular hyperplasia, adrenalcarcinomas, pituitary adenomas, pituitary adenocarcinomas, carincinoidtumors, neuroendocrine tumors, or combinations thereof. Treatment ofendogenous Cushing's syndrome includes administration of a therapeuticdrug, e.g., aminoglutethimide (Cytadren®), and mitotane (Lysodren),and/or surgery. Surgical removal of the ACTH-secreting tumor orcortisol-secreting tumor is invariably followed by secondary adrenalinsufficiency and the need for glucocorticoid replacement therapy. Theduration of secondary adrenal insufficiency can vary and glucocorticoidreplacement therapy is maintained until the adrenal function recovers tonormal, healthy function. The methods provided herein can significantlyexpedite the recovery of the patient's HPA axis.

In cases when secondary adrenal insufficiency is due to a structuralpituitary or hypothalamic abnormality (e.g., patients withhypophysectomy, patients with pituitary apoplexy, or any other conditionleading to destruction of those glands), the methods of the presentinvention may not be useful. Administration of a GRA and a GC requiresan anatomically intact hypothalamus and pituitary, or at least the partof those glands involved in the regulation and production of CRH andACTH should be intact.

Generally, a clinician diagnoses secondary adrenal insufficiency inpatients presenting with one or more symptoms of the disorder byevaluating the patient's medical history. Further diagnostic testing maynot be needed if the patient has had complete removal of a pituitary orhypothalamus tumor. If the patient has had partial surgery of thepituitary, hypothalamus or adrenal glands, or is suspected of havingACTH deficiency, further diagnostic assays to detect cortisol levels maybe performed.

Non-limiting examples of such diagnostic or detection assays include thelow dose ACTH stimulation test, corticotropin-releasing hormone (CRH)stimulation test, low-dose dexamethasone test, assays to detect totaland/or free cortisol levels in, for example, serum, plasma, saliva,urine, or feces, and assays to detect ACTH levels. In the low dose ACTHstimulation test, levels of ACTH and cortisol are measured beforeadministration of the synthetic derivative of ACTH (cosyntropin,Cortrosyn®). A second cortisol measurement is taken one hour later. Ifthe level of cortisol remains substantially unchanged or is less thanabout 17 μg/dL after administration of cosyntropin, secondary adrenalinsufficiency may be indicated. The patient's adrenal glands may beevaluated by CT scan to detect abnormal size or possible impairment. Insome cases, a CT scan or MRI of the brain is performed to assess thepresence of a pituitary tumor or atrophy.

Patients with secondary adrenal insufficiency have lower than normallevels of cortisol in the morning. For example, such a patient may havea serum cortisol level of less than 4 μg/dL between 7 a.m. to 9 a.m. Insome embodiments, the method disclosed herein is useful to treat apatient with secondary adrenal insufficiency and a basal cortisol (e.g.,basal total cortisol or basal free cortisol) level of less than 12μg/dL, e.g., 11.5 μg/dL, 11 μg/dL, 10 μg/dL, 9 μg/dL, 8 μg/dL, 7 μg/dL,6 μg/dL, 5 μg/dL, 4 μg/dL, 3 μg/dL, 2 μg/dL, 1 μg/dL, or less than 1μg/dL. A patient's basal cortisol level can be measured in plasma,serum, saliva, urine, and the like. In some instances, a patient withsecondary adrenal insufficiency has a basal plasma or serum cortisollevel of less than 12 μg/dL, e.g., 11.5 μg/dL, 11 μg/dL, 10 μg/dL, 9μg/dL, 8 μg/dL, 7 μg/dL, 6 μg/dL, 5 μg/dL, 4 μg/dL, 3 μg/dL, 2 μg/dL, 1μg/dL, or less than 1 μg/dL.

In some aspects of the present disclosure, the patient is not beingadministered a combination treatment comprising a GRA and a GC. In otherwords, the patient is treatment naïve. In some embodiments, the patientreceiving a therapeutically effective amount of a GRA in combinationwith a GC, according to the methods described herein, is not beentreated for a disorder or condition selected from the group consistingof glaucoma, inflammatory diseases, rheumatoid arthritis, asthma andrhinitis, chronic pulmonary disease, allergies, and autoimmune diseases.In other embodiments, the patient is not receiving a therapeuticallyeffective amount of a GRA in combination with a therapeuticallyeffective amount of a GC to reduce one or more side effects ofglucocorticoid treatment. The side effects can be of weight gain,glaucoma, fluid retention, increased blood pressure, mood swings,cataracts, high blood sugar, diabetes, infection, loss of calcium frombones, osteoporosis, menstrual irregularities, fat redistribution,growth retardation, cushingoid appearance, or any combination thereof.

The methods disclosed herein can be used to treat a patient withsecondary adrenal insufficiency, with the proviso that the patient notbe otherwise in need of treatment with a combination treatment of aglucocorticoid receptor antagonist and a glucocorticoid.

B. Glucocorticoid Receptor Antagonists

The methods of the present invention generally provide administering aglucocorticoid receptor antagonist. In some cases, the glucocorticoidreceptor antagonist is a specific glucocorticoid receptor antagonist. Asused herein, a specific glucocorticoid receptor antagonist refers to acomposition or compound which inhibits any biological responseassociated with the binding of a glucocorticoid receptor to an agonistby preferentially binding to the glucocorticoid receptor rather thananother nuclear receptor (NR). In some embodiments, the specificglucocorticoid receptor antagonist binds preferentially toglucocorticoid receptor rather than the mineralocorticoid receptor (MR),androgen receptor (AR), or progesterone receptor (PR). In an exemplaryembodiment, the specific glucocorticoid receptor antagonist bindspreferentially to glucocorticoid receptor rather than themineralocorticoid receptor (MR). In another exemplary embodiment, thespecific glucocorticoid receptor antagonist binds preferentially toglucocorticoid receptor rather than the progesterone receptor (PR). Inanother exemplary embodiment, the specific glucocorticoid receptorantagonist binds preferentially to glucocorticoid receptor rather thanthe androgen receptor (AR). In yet another exemplary embodiment, thespecific glucocorticoid receptor antagonist binds preferentially toglucocorticoid receptor in comparison to MR and PR, MR and AR, PR andAR, or MR, PR, and AR.

In a related embodiment, the specific glucocorticoid receptor antagonistbinds to the glucocorticoid receptor with an association constant(K_(d)) that is at least 10-fold less than the K_(d) for other nuclearreceptors. In another embodiment, the specific glucocorticoid receptorantagonist binds to the glucocorticoid receptor with an associationconstant (K_(d)) that is at least 100-fold less than the K_(d) for theother nuclear receptors. In another embodiment, the specificglucocorticoid receptor antagonist binds to the glucocorticoid receptorwith an association constant (K_(d)) that is at least 1000-fold lessthan the K_(d) for the other nuclear receptors.

Generally, treatment can be provided by administering an effectiveamount of a glucocorticoid receptor antagonist (GRA) of any chemicalstructure or mechanism of action and a glucocorticoid of any chemicalstructure or mechanism of action. Provided herein, are classes ofexemplary GRAs and specific members of such classes. However, one ofskill in the art will readily recognize other related or unrelated GRAsthat can be employed in the treatment methods described herein.

1. GRAs Having a Steroidal Backbone

In some embodiments, an effective amount of a GRA with a steroidalbackbone is administered to a subject for treatment of an ACTH-secretingtumor. Steroidal GRAs can be obtained by modification of the basicstructure of glucocorticoid agonists, i.e., varied forms of the steroidbackbone. The structure of cortisol can be modified in a variety ofways. The two most commonly known classes of structural modifications ofthe cortisol steroid backbone to create GRAs include modifications ofthe 11-β hydroxy group and modification of the 17-3 side chain (See,e.g., Lefebvre, J. Steroid Biochem. 33:557-563, 1989).

Examples of steroidal GR antagonists include androgen-type steroidalcompounds as described in U.S. Pat. No. 5,929,058, and the compoundsdisclosed in U.S. Pat. Nos. 4,296,206; 4,386,085; 4,447,424; 4,477,445;4,519,946; 4,540,686; 4,547,493; 4,634,695; 4,634,696; 4,753,932;4,774,236; 4,808,710; 4,814,327; 4,829,060; 4,861,763; 4,912,097;4,921,638; 4,943,566; 4,954,490; 4,978,657; 5,006,518; 5,043,332;5,064,822; 5,073,548; 5,089,488; 5,089,635; 5,093,507; 5,095,010;5,095,129; 5,132,299; 5,166,146; 5,166,199; 5,173,405; 5,276,023;5,380,839; 5,348,729; 5,426,102; 5,439,913; 5,616,458, 5,696,127, and6,303,591. Such steroidal GR antagonists include cortexolone,dexamethasone-oxetanone, 19-nordeoxycorticosterone, 19-norprogesterone,cortisol-21-mesylate; dexamethasone-21-mesylate,11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9-estradien-3-one(RU009), and(17α)-17-hydroxy-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one (RU044).

Other examples of steroidal antiglucocorticoids are disclosed in VanKampen et al. (2002) Eur. J. Pharmacol. 457(2-3):207, WO 03/043640, EP 0683 172 B1, and EP 0 763 541 B1, each of which is incorporated herein byreference. EP 0 763 541 B1 and Hoyberg et al., Int'l J. ofNeuro-psychopharmacology, 5:Supp. 1, S148 (2002); disclose the compound(11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one(ORG 34517) which in one embodiment, is administered in an amounteffective to treat an ACTH-secreting tumor in a subject.

2. Removal or Substitution of the 11-β Hydroxy Group

Glucocorticoid antagonists with modified steroidal backbones comprisingremoval or substitution of the 11-β hydroxy group are administered inone embodiment of the invention. This class includes natural GRAs,including cortexolone, progesterone and testosterone derivatives, andsynthetic compositions, such as mifepristone (Lefebvre, et al. supra).Preferred embodiments of the invention include all 11-β aryl steroidbackbone derivatives because, in some cases, these compounds can bedevoid of progesterone receptor (PR) binding activity (Agarwal, FEBS217:221-226, 1987). In another embodiment an 11-β phenyl-aminodimethylsteroid backbone derivative, which is both an effectiveanti-glucocorticoid and anti-progesterone agent, is administered. Thesecompositions can act as reversibly-binding steroid receptor antagonists.For example, when bound to a 11-β phenyl-aminodimethyl steroid, thesteroid receptor can be maintained in a conformation that cannot bindits natural ligand, such as cortisol in the case of GR (Cadepond, 1997,supra).

Synthetic 11-beta phenyl-aminodimethyl steroids include mifepristone,also known as RU486, or17-β-hydrox-11-β-(4-dimethyl-aminophenyl)17-α-(1-propynyl)estra-4,9-dien-3-one).Mifepristone has been shown to be a powerful antagonist of both theprogesterone and glucocorticoid (GR) receptors. Thus, in someembodiments, the GRA administered to treat an ACTH-secreting tumor ismifepristone, or a salt, tautomer, or derivative thereof. In otherembodiments, however, administration of mifepristone is specificallyexcluded as a GRA for treatment of an ACTH-secreting tumor.

Another 11-β phenyl-aminodimethyl steroid shown to have GR antagonisteffects includes the dimethyl aminoethoxyphenyl derivative RU009(RU39.009),11-β-(4-dimethyl-aminoethoxyphenyl)-17-α-(propynyl-17-β-hydroxy-4,9-estradien-3-one)(see Bocquel, J. Steroid Biochem. Molec. Biol. 45:205-215, 1993).Another GR antagonist related to RU486 is RU044 (RU43.044)17-β-hydrox-17-α-19-(4-methyl-phenyl)-androsta-4,9(11)-dien-3-one)(Bocquel, 1993, supra). See also Teutsch, Steroids 38:651-665, 1981;U.S. Pat. Nos. 4,386,085 and 4,912,097.

One embodiment includes compositions that are irreversibleanti-glucocorticoids. Such compounds include α-keto-methanesulfonatederivatives of cortisol, including cortisol-21-mesylate(4-pregnene-11-β, 17-α, 21-triol-3, 20-dione-21-methane-sulfonate anddexamethasone-21-mesylate (16-methyl-9-α-fluoro-1,4-pregnadiene-11 β,17-α, 21-triol-3, 20-dione-21-methane-sulfonte). See Simons, J. SteroidBiochem. 24:25-32, 1986; Mercier, J. Steroid Biochem. 25:11-20, 1986;U.S. Pat. No. 4,296,206.

3. Modification of the 17-beta Side Chain Group

Steroidal anti-glucocorticoids which can be obtained by variousstructural modifications of the 17-β side chain are also used in themethods of the invention. This class includes syntheticantiglucocorticoids such as dexamethasone-oxetanone, various 17,21-acetonide derivatives and 17-beta-carboxamide derivatives ofdexamethasone (Lefebvre, 1989, supra; Rousseau, Nature 279:158-160,1979).

4. Other Steroid Backbone Modifications

GRAs used in the various embodiments of the invention include anysteroid backbone modification which effects a biological responseresulting from a GR-agonist interaction. Steroid backbone antagonistscan be any natural or synthetic variation of cortisol, such as adrenalsteroids missing the C-19 methyl group, such as19-nordeoxycorticosterone and 19-norprogesterone (Wynne, Endocrinology107:1278-1280, 1980).

In general, the 11-β side chain substituent, and particularly the sizeof that substituent, can play a key role in determining the extent of asteroid's antiglucocorticoid activity. Substitutions in the A ring ofthe steroid backbone can also be important. For example,17-hydroxypropenyl side chains can, in some cases, decreaseantiglucocorticoid activity in comparison to 17-propynyl side chaincontaining compounds.

Additional glucocorticoid receptor antagonists known in the art andsuitable for practice of the invention include21-hydroxy-6,19-oxidoprogesterone (See Vicent, Mol. Pharm. 52:749-753,1997), Org31710 (See Mizutani, J Steroid Biochem Mol Biol 42(7):695-704,1992), RU43044, RU40555 (See Kim, J Steroid Biochem Mol Biol.67(3):213-22, 1998), and RU28362.

5. Non-Steroidal Anti-Glucocorticoids as Antagonists

Non-steroidal glucocorticoid antagonists (GRAs) are also used in themethods of the invention to treat adrenal insufficiency in a subject.These include synthetic mimetics and analogs of proteins, includingpartially peptidic, pseudopeptidic and non-peptidic molecular entities.For example, oligomeric peptidomimetics useful in the invention include(α-β-unsaturated) peptidosulfonamides, N-substituted glycinederivatives, oligo carbamates, oligo urea peptidomimetics,hydrazinopeptides, oligosulfones and the like (See, e.g., Amour, Int. J.Pept. Protein Res. 43:297-304, 1994; de Bont, Bioorganic &MedicinalChem. 4:667-672, 1996).

Examples of non-steroidal GR antagonists include the GR antagonistcompounds disclosed in U.S. Pat. Nos. 5,696,127; 6,570,020; and6,051,573; the GR antagonist compounds disclosed in US PatentApplication 20020077356, the glucocorticoid receptor antagonistsdisclosed in Bradley et al., J. Med. Chem. 45, 2417-2424 (2002), e.g.,4α(S)-benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol(“CP 394531”) and4α(S)-benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol(“CP 409069”); and the compounds disclosed in PCT InternationalApplication No. WO 96/19458, which describes non-steroidal compoundswhich are high-affinity, highly selective antagonists for steroidreceptors, such as 6-substituted-1,2-dihydro-N-protected-quinolines.

In some embodiments, adrenal insufficiency is treated with an effectiveamount of a non-steroidal GRA having a cyclohexyl-pyrimidine backbone, afused azadecalin backbone, a heteroaryl ketone fused azadecalinbackbone, or an octahydro fused azadecalin backbone. For example,adrenal insufficiency can be treated with effective amounts of one ofthe foregoing GRAs and a GC or a GC analog. Exemplary GRAs having acyclohexyl-pyrimidine backbone include those described in U.S. Pat. No.8,685,973. In some cases, the GRA having a cyclohexyl-pyrimidinebackbone has the following structure:

wherein

-   -   the dashed line is absent or a bond;    -   X is selected from the group consisting of O and S;    -   R¹ is selected from the group consisting of cycloalkyl,        heterocycloalkyl, aryl and heteroaryl, optionally substituted        with from 1 to 3 R^(1a) groups;    -   each R^(1a) is independently selected from the group consisting        of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆        alkyl-OR^(1b), halogen, C₁₋₆ haloalkyl, C₁₋₆ haloaloxy,        —OR^(1b), —NR^(1b)R^(1c), —C(O)R^(1b), —C(O)OR^(1b),        —OC(O)R^(1b), —C(O)NR^(1b)R^(1c), —NR^(1b)C(O)R^(1c),        —SO₂R^(1b), —SO₂NR^(1b)R^(1c), cycloalkyl, heterocycloalkyl,        aryl and heteroaryl;    -   R^(1b) and R^(1c) are each independently selected from the group        consisting of H and C₁₋₆ alkyl;    -   R² is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆        alkyl-OR^(1b), C₁₋₆ alkyl-NR^(1b)R^(1c) and C₁₋₆        alkylene-heterocycloalkyl;    -   R³ is selected from the group consisting of H and C₁₋₆ alkyl;    -   Ar is aryl, optionally substituted with 1-4 R⁴ groups;    -   each R⁴ is independently selected from the group consisting of        H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, C₁₋₆ haloalkyl and C₁₋₆        haloalkoxy;    -   L¹ is a bond or C₁₋₆ alkylene; and    -   subscript n is an integer from 0 to 3,        or a salts and isomers thereof.

Exemplary GRAs having a fused azadecalin backbone include thosedescribed in U.S. Pat. Nos. 7,928,237; and 8,461,172. In some cases, theGRA having a fused azadecalin backbone has the following structure:

-   -   wherein    -   L¹ and L² are members independently selected from a bond and        unsubstituted alkylene;    -   R¹ is a member selected from unsubstituted alkyl, unsubstituted        heteroalkyl, unsubstituted heterocycloalkyl, —OR^(1A),        —NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), and —C(O)OR^(1A), wherein    -   R^(1A) is a member selected from hydrogen, unsubstituted alkyl        and unsubstituted heteroalkyl,    -   R^(1C) and R^(1D) are members independently selected from        unsubstituted alkyl and unsubstituted heteroalkyl,    -   wherein R^(1C) and R^(1D) are optionally joined to form an        unsubstituted ring with the nitrogen to which they are attached,        wherein said ring optionally comprises an additional ring        nitrogen;    -   R² has the formula:

-   -   wherein    -   R^(2G) is a member selected from hydrogen, halogen,        unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted        cycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃;    -   J is phenyl;    -   t is an integer from 0 to 5;    -   X is —S(O₂)—; and    -   R⁵ is phenyl optionally substituted with 1-5 R^(5A) groups,        wherein    -   R^(5A) is a member selected from hydrogen, halogen, —OR^(5A1),        —S(O₂)NR^(5A2)R^(5A3), —CN, and unsubstituted alkyl, wherein    -   R^(5A1) is a member selected from hydrogen and unsubstituted        alkyl, and    -   R^(5A2) and R^(5A3) are members independently selected from        hydrogen and unsubstituted alkyl,        or salts and isomers thereof.

Exemplary GRAs having a heteroaryl ketone fused azadecalin backboneinclude those described in U.S. 2014/0038926. In some cases, the GRAhaving a heteroaryl ketone fused azadecalin backbone has the followingstructure:

wherein

-   -   R¹ is a heteroaryl ring having from 5 to 6 ring members and from        1 to 4 heteroatoms each independently selected from the group        consisting of N, O and S, optionally substituted with 1-4 groups        each independently selected from R^(1a);    -   each R^(1a) is independently selected from the group consisting        of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, —CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈        heterocycloalkyl;    -   ring J is selected from the group consisting of a cycloalkyl        ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl        ring, wherein the heterocycloalkyl and heteroaryl rings have        from 5 to 6 ring members and from 1 to 4 heteroatoms each        independently selected from the group consisting of N, O and S;    -   each R² is independently selected from the group consisting of        hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN, —OH, —NR^(2a)R^(2b),        —C(O)R^(2a), —C(O)OR²a, —C(O)NR^(2a)R^(2b), —SR^(2a),        —S(O)R^(2a), —S(O)₂ R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈        heterocycloalkyl, wherein the heterocycloalkyl groups are        optionally substituted with 1-4 R², groups;    -   alternatively, two R² groups linked to the same carbon are        combined to form an oxo group (═O);    -   alternatively, two R² groups are combined to form a        heterocycloalkyl ring having from 5 to 6 ring members and from 1        to 3 heteroatoms each independently selected from the group        consisting of N, O and S, wherein the heterocycloalkyl ring is        optionally substituted with from 1 to 3 R^(2d) groups;    -   R^(2a) and R^(2b) are each independently selected from the group        consisting of hydrogen and C₁₋₆ alkyl;    -   each R^(2c) is independently selected from the group consisting        of hydrogen, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,        —CN, and —NR^(2a)R^(2b);    -   each R^(2d) is independently selected from the group consisting        of hydrogen and C₁₋₆ alkyl, or two R^(2d) groups attached to the        same ring atom are combined to form (═O);    -   R³ is selected from the group consisting of phenyl and pyridyl,        each optionally substituted with 1-4 R^(3a) groups;    -   each R^(3a) is independently selected from the group consisting        of hydrogen, halogen, and C₁₋₆ haloalkyl; and    -   subscript n is an integer from 0 to 3;    -   or salts and isomers thereof.

Exemplary GRAs having an octohydro fused azadecalin backbone includethose described in U.S. Provisional Patent Appl. No. 61/908,333,entitled Octahydro Fused Azadecalin Glucocorticoid Receptor Modulators,Attorney Docket No. 85178-887884 (007800US), filed on Nov. 25, 2013. Insome cases, the GRA having an octohydro fused azadecalin backbone hasthe following structure:

wherein

-   -   R¹ is a heteroaryl ring having from 5 to 6 ring members and from        1 to 4 heteroatoms each independently selected from the group        consisting of N, O and S, optionally substituted with 1-4 groups        each independently selected from R^(1a);    -   each R^(1a) is independently selected from the group consisting        of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl;    -   ring J is selected from the group consisting of an aryl ring and        a heteroaryl ring having from 5 to 6 ring members and from 1 to        4 heteroatoms each independently selected from the group        consisting of N, O and S;    -   each R² is independently selected from the group consisting of        hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN, —OH, —NR^(2a)R^(2b),        —C(O)R^(2a), —C(O)OR²a, —C(O)NR^(2a)R^(2b), —SR^(2a),        —S(O)R^(2a), —S(O)₂ R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈        heterocycloalkyl having from 1 to 3 heteroatoms each        independently selected from the group consisting of N, O and S;    -   alternatively, two R² groups on adjacent ring atoms are combined        to form a heterocycloalkyl ring having from 5 to 6 ring members        and from 1 to 3 heteroatoms each independently selected from the        group consisting of N, O and S, wherein the heterocycloalkyl        ring is optionally substituted with from 1 to 3 R^(2c) groups;    -   R^(2a), R^(2b) and R^(2c) are each independently selected from        the group consisting of hydrogen and C₁₋₆ alkyl;    -   each R^(3a) is independently halogen; and    -   subscript n is an integer from 0 to 3;        or salts and isomers thereof.

C. Glucocorticoids

The methods of the present invention generally include administering aglucocorticoid, a synthetic glucocorticoid or a functional derivativethereof. A glucocorticoid includes any chemical compound that can bindto and activate the glucocorticoid receptor. In some embodiments, thesynthetic glucocorticoid is hydrocortisone, prednisone, prednisolone,dexamethasone, a glucocorticoid analogue, a synthetic glucocorticoidanalogue, derivatives thereof, or any combination thereof.

Non-limiting examples of synthetic glucocorticoids that can be used inthe present invention include beclomethasone dipropionate,betamethasone, betamethasone acetate, betamethasone benzoate,betamethasone disodium phosphate, cortisone acetate, dexamethasone,dexamethasone sodium phosphate, fludrocortisone acetate, flunisolide,fluoncinolone acetonide, fluocinonide, flurandrenolide, deflazacort,methylprednisolone, methylprednisolone acetate, methylprednisolonesodium succinnate, prednisolone, prednisolone acetate, prednisolonesodium phosphate, prednisolone tebutate, prednisone, triamcinolone,triamcinolone acetonide, triamcinolone diacetate and triamcinolonehexaacetonide, including pharmaceutically acceptable esters, salts andcomplexes thereof.

In some embodiments, the present invention provides a pharmaceuticalcomposition including a compound of the present invention and apharmaceutically acceptable excipient. In some embodiments, the presentinvention provides a pharmaceutical composition including aglucocorticoid receptor antagonist of the present invention and apharmaceutically acceptable excipient. In some embodiments, the presentinvention provides a pharmaceutical composition including aglucocorticoid of the present invention and a pharmaceuticallyacceptable excipient. In some embodiments, the present inventionprovides a pharmaceutical composition including a glucocorticoidreceptor antagonist and a glucocorticoid of the present invention and apharmaceutically acceptable excipient.

D. Pharmaceutical Compositions of Glucocorticoid Receptor Antagonistsand Glucocorticoids

The GRA and/or GC compositions of the present invention can be preparedin a wide variety of oral, parenteral and topical dosage forms. Oralpreparations of either include tablets, pills, powder, dragees,capsules, liquids, lozenges, cachets, gels, syrups, slurries,suspensions, etc., suitable for ingestion by the patient. The GRA and/orGC compositions of the present invention can also be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, the GRAand/or GC compositions described herein can be administered byinhalation, for example, intranasally. Additionally, the GRA and/or GCcompositions of the present invention can be administered transdermally.The GRA and/or GC compositions of this invention can also beadministered by intraocular, intravaginal, and intrarectal routesincluding suppositories, insufflation, powders and aerosol formulations(for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol.35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111,1995). Accordingly, the present invention provides pharmaceuticalcompositions of a GRA including a pharmaceutically acceptable carrier orexcipient and a GRA compound of the present invention. The presentinvention provides pharmaceutical compositions of a GC including apharmaceutically acceptable carrier or excipient and a GC compound ofthe present invention.

For preparing pharmaceutical compositions from the GRA or GC compoundsof the present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances, which may alsoact as diluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material. Details ontechniques for formulation and administration are well described in thescientific and patent literature, see, e.g., the latest edition ofRemington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa.(“Remington's”).

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5% or 10% to70% of the compounds of the present invention.

Suitable solid excipients include, but are not limited to, magnesiumcarbonate; magnesium stearate; talc; pectin; dextrin; starch;tragacanth; a low melting wax; cocoa butter; carbohydrates; sugarsincluding, but not limited to, lactose, sucrose, mannitol, or sorbitol,starch from corn, wheat, rice, potato, or other plants; cellulose suchas methyl cellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins including, but not limited to, gelatin and collagen. Ifdesired, disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can contain thecompounds of the present invention mixed with a filler or binders suchas lactose or starches, lubricants such as talc or magnesium stearate,and, optionally, stabilizers. In soft capsules, the compounds of thepresent invention may be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycol withor without stabilizers.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the compoundsof the present invention are dispersed homogeneously therein, as bystirring. The molten homogeneous mixture is then poured into convenientsized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingone or more compounds of the present invention in water and addingsuitable colorants, flavors, stabilizers, and thickening agents asdesired. Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, anddispersing or wetting agents such as a naturally occurring phosphatide(e.g., lecithin), a condensation product of an alkylene oxide with afatty acid (e.g., polyoxyethylene stearate), a condensation product ofethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethylene oxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol (e.g.,polyoxyethylene sorbitol mono-oleate), or a condensation product ofethylene oxide with a partial ester derived from fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can be formulated by suspending the compounds of thepresent invention in a vegetable oil, such as arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin;or a mixture of these. The oil suspensions can contain a thickeningagent, such as beeswax, hard paraffin or cetyl alcohol. Sweeteningagents can be added to provide a palatable oral preparation, such asglycerol, sorbitol or sucrose. These formulations can be preserved bythe addition of an antioxidant such as ascorbic acid. As an example ofan injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.281:93-102, 1997. The pharmaceutical formulations of the invention canalso be in the form of oil-in-water emulsions. The oily phase can be avegetable oil or a mineral oil, described above, or a mixture of these.Suitable emulsifying agents include naturally-occurring gums, such asgum acacia and gum tragacanth, naturally occurring phosphatides, such assoybean lecithin, esters or partial esters derived from fatty acids andhexitol anhydrides, such as sorbitan mono-oleate, and condensationproducts of these partial esters with ethylene oxide, such aspolyoxyethylene sorbitan mono-oleate. The emulsion can also containsweetening agents and flavoring agents, as in the formulation of syrupsand elixirs. Such formulations can also contain a demulcent, apreservative, or a coloring agent.

The GRA and/or GC compositions of the present invention can also bedelivered as microspheres for slow release in the body. For example,microspheres can be formulated for administration via intradermalinjection of drug-containing microspheres, which slowly releasesubcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; asbiodegradable and injectable gel formulations (see, e.g., Gao Pharm.Res. 12:857-863, 1995); or, as microspheres for oral administration(see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Bothtransdermal and intradermal routes afford constant delivery for weeks ormonths.

In another embodiment, the GRA and/or GC compositions of the presentinvention can be formulated for parenteral administration, such asintravenous (IV) administration or administration into a body cavity orlumen of an organ. The formulations for administration will commonlycomprise a solution of the compositions of the present inventiondissolved in a pharmaceutically acceptable carrier. Among the acceptablevehicles and solvents that can be employed are water and Ringer'ssolution, an isotonic sodium chloride. In addition, sterile fixed oilscan conventionally be employed as a solvent or suspending medium. Forthis purpose any bland fixed oil can be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid canlikewise be used in the preparation of injectables. These solutions aresterile and generally free of undesirable matter. These GRA and/or GCformulations may be sterilized by conventional, well known sterilizationtechniques. The formulations may contain pharmaceutically acceptableauxiliary substances as required to approximate physiological conditionssuch as pH adjusting and buffering agents, toxicity adjusting agents,e.g., sodium acetate, sodium chloride, potassium chloride, calciumchloride, sodium lactate and the like. The concentration of thecompositions of the present invention in these formulations can varywidely, and will be selected primarily based on fluid volumes,viscosities, body weight, and the like, in accordance with theparticular mode of administration selected and the patient's needs. ForIV administration, the GRA and/or GC formulation can be a sterileinjectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension can be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation can also be asterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In another embodiment, the formulations of the compositions of thepresent invention can be delivered by the use of liposomes which fusewith the cellular membrane or are endocytosed, i.e., by employingligands attached to the liposome, or attached directly to theoligonucleotide, that bind to surface membrane protein receptors of thecell resulting in endocytosis. By using liposomes, particularly wherethe liposome surface carries ligands specific for target cells, or areotherwise preferentially directed to a specific organ, one can focus thedelivery of the compositions of the present invention into the targetcells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306,1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J.Hosp. Pharm. 46:1576-1587, 1989).

Lipid-based drug delivery systems include lipid solutions, lipidemulsions, lipid dispersions, self-emulsifying drug delivery systems(SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). Inparticular, SEDDS and SMEDDS are isotropic mixtures of lipids,surfactants and co-surfactants that can disperse spontaneously inaqueous media and form fine emulsions (SEDDS) or microemulsions(SMEDDS). Lipids useful in the formulations of the present inventioninclude any natural or synthetic lipids including, but not limited to,sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters,glycerol esters, Labrafil®, Labrasol®, Cremophor®, Solutol®, Tween®,Capryol®, Capmul®, Captex®, and Peceol®.

The GRA and/or GC composition can also contain other compatibletherapeutic agents. The compounds described herein can be used incombination with one another, with other active agents known to beuseful in antagonizing a glucocorticoid receptor, or with adjunctiveagents that may not be effective alone, but may contribute to theefficacy of the active agent.

E. Methods of Administration

The GRA and/or GC compounds or compositions of the present invention canbe delivered by any suitable means, including oral, parenteral (e.g.,intravenous injection or intramuscular injection) and topical methods.Transdermal administration methods, by a topical route, can beformulated as applicator sticks, solutions, suspensions, emulsions,gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.Accordingly, the GC compounds described herein can be administered in anoral dosage form or an injection dosage form.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the compounds and compositions of the presentinvention. The unit dosage form can be a packaged preparation, thepackage containing discrete quantities of preparation, such as packetedtablets, capsules, and powders in vials or ampoules. Also, the unitdosage form can be a capsule, tablet, cachet, or lozenge itself, or itcan be the appropriate number of any of these in packaged form.

GRAs can be administered orally. For example, the GRA can beadministered as a pill, a capsule, or liquid formulation as describedherein. Alternatively, GRAs can be provided via parenteraladministration. For example, the GRA can be administered intravenously(e.g., by injection or infusion). Similarly, the GC can be administeredorally, e.g., as a pill, a capsule or liquid formulation. Alternatively,the GC can be administered via parenteral administration, e.g.,intravenously. Additional methods of administration of the compoundsdescribed herein, and pharmaceutical compositions or formulationsthereof, are described below.

The GRA and GC compounds and compositions of the present invention canbe co-administered. Co-administration includes administering the GRAcompound or composition of the present invention within 0.5, 1, 2, 4, 6,8, 10, 12, 16, 20, or 24 hours of the GC compound or composition of thepresent invention. Co-administration also includes administeringsimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.Moreover, the compounds and compositions of the present invention caneach be administered once a day, or two, three, or more times per day soas to provide the preferred dosage level per day.

In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding the compounds and compositions of the present invention andany other agent. Alternatively, the various components can be formulatedseparately.

Secondary adrenal insufficiency can be treated in a subject in needthereof, by simultaneously or sequentially administering to the subjecti) a glucocorticoid receptor antagonist (GRA); and ii) glucocorticoid(GC), in effective amounts such that the patient's morning plasmacortisol level is at least 12 μg/dL. The GRA and GC can be administeredin a single (i.e., combined) dose form, or as a GRA dose and a GC dose.The GRA can be administered first, followed by a second administrationof the GC. Alternatively, the GC can be administered first, followed bya second administration of the GRA.

Glucocorticoid receptor antagonists (GRAs) can be administeredsimultaneously or sequentially with a glucocorticoid (e.g.,glucocorticoid or an analog thereof) at a dose of from about 0.1 mg toabout 10,000 mg, about 1 mg to about 1000 mg, about 10 mg to about 750mg, about 25 mg to about 500 mg, about 50 mg to about 250 mg, or about75 mg to about 150 mg of the GRA. In some cases, GRAs can beadministered simultaneously or sequentially with a glucocorticoid (e.g.,glucocorticoid or an analog thereof) at a dose of about 1, 5, 10, 20,30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900or 1000 mg of the GRA. In some cases, GRAs can be administeredsimultaneously or sequentially with a glucocorticoid (e.g.,glucocorticoid or an analog thereof) at a dose of about 0.1, 0.25, 0.5,0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100, 125, or 150mg/kg of the GRA. In other cases, one or more of the foregoing GRAdosages or a dose within one of the foregoing GRA dose ranges can beadministered about four times per day, three times per day, once perday, semi-weekly, weekly, bi-weekly, or monthly. In yet other cases, asubject is administered a high dose (e.g., 500 mg or more) of GRA for aperiod of time (e.g., twice per day for one week) and then administereda low dose (e.g., 100 mg or less) of GRA for a period of time.Alternatively, a subject can be administered a low dose (e.g., 150 mg orless) of GRA for a period of time (e.g., every other day for one week ormore) and then administered a high dose (e.g., 600 mg or more) of GRAfor a period of time (e.g., daily). For example, the treatment course ofthe GRA can follow the schedule of: a) 150 mg every other day for twomonths, b) 300 mg every other day for one month, c) 300 mg daily for onemonth, d) 600 mg daily for three months, and e) 300 mg every other dayfor two months.

Glucocorticoids (e.g., glucocorticoid or an GC) can be administeredsimultaneously or sequentially with a GRA at a dose of from about 0.1 mgto about 10,000 mg, about 1 mg to about 1000 mg, about 10 mg to about750 mg, about 25 mg to about 500 mg, about 50 mg to about 250 mg, orabout 75 mg to about 150 mg of the glucocorticoid. In some cases, theglucocorticoid can be administered simultaneously or sequentially with aGRA at a dose of about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100,200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg of the glucocorticoid.In other cases, glucocorticoid can be administered simultaneously orsequentially with a GRA at a dose of about 0.1, 0.25, 0.5, 0.75, 1, 1.5,2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100, 125, or 150 mg/kg of theglucocorticoid. In some embodiments, one or more of the foregoingdosages of glucocorticoid or a dose within one of the foregoing doseranges of glucocorticoid can be administered about four times per day,three times per day, once per day, semi-weekly, weekly, bi-weekly, ormonthly. The effective amount of unit dose can be about 0.25 mg, 0.5 mg,1.0 mg, 2.0 mg, 5.0 mg, 10 mg, 20 mg and 30 mg per unit dosage.

In some cases, a subject is administered a high dose (e.g., 30 mg ormore) of glucocorticoid for a period of time (e.g., twice per day forone week) and then administered a low dose (e.g., 10 mg or less) ofglucocorticoid for a period of time. In yet other cases, a subject isadministered a low dose (e.g., 10 mg or less) of glucocorticoid for aperiod of time (e.g., twice per day for one week) and then administereda high dose (e.g., 30 mg or more) of glucocorticoid for a period oftime. For example, the treatment course of hydrocortisone can follow theschedule of: a) 15 mg daily for 5 months, and b) 10 mg daily for onemonth.

The dosage schedule and amounts effective for this use, i.e., the“dosing regimen,” will depend upon a variety of factors, including theseverity of the disease, the disease etiology, the patient's physicalstatus, age and the like. In calculating the dosage regimen for apatient, the mode of administration also is taken into consideration.The dosage regimen also takes into consideration pharmacokineticsparameters well known in the art, i.e., the GRA's and/or GC's rate ofabsorption, bioavailability, metabolism, clearance, and the like (see,e.g., Hidalgo-Aragones, J. Steroid Biochem. Mol. Biol. 58:611-617, 1996;Groning, Pharmazie 51:337-341, 1996; Fotherby, Contraception 54:59-69,1996; Johnson, J. Pharm. Sci. 84:1144-1146, 1995; Rohatagi, Pharmazie50:610-613, 1995; Brophy, Eur. J. Clin. Pharmacol. 24:103-108, 1983;Remington's Pharmaceutical Science, supra).

F. Methods of Determining Treatment Efficacy

Any one or more of the foregoing detection methods described herein, orknown generally in the art, can be used to assess the efficacy of thetreatment. In some embodiments, a subject with secondary adrenalinsufficiency is treated by administering effective amounts of a GRA anda GC that increase the subject's morning cortisol level, e.g., basalcortisol level to at least 12 μg/dL, and the treatment can be monitoredto determined its efficacy. For example, efficacy can be indicated bydetecting the level of plasma, serum, urine, or saliva basal cortisol,e.g., basal total or free cortisol. In some embodiments,co-administration of a therapeutically effective amount of a GC and atherapeutically effective amount of a GRA affects the patient's basalplasma cortisol level such that it is 12 μg/dL or higher, or acomparable level in another biological sample. In other embodiments,co-administration of a therapeutically effective amount of a GC and atherapeutically effective amount of a GRA changes the patient's basalserum cortisol level such that the level is 12 μg/dL or higher, or acomparable level in another biological sample.

As described above, an individual's cortisol level is regulated by ACTHwhich is synthesized in the pituitary in response to corticotropinreleasing hormone (CRH) from the hypothalamus. Cortisol is mostly foundbound to glucocorticoid-binding globulin and albumin. Free circulating,unbound cortisol is the physiologically active form and is <5% of totalcortisol. Without being bound to any particular therapy,co-administration of a glucocorticoid and a glucocorticoid receptorantagonist can stimulate an individual to secrete cortisol in themorning.

Cortisol levels can be measured in serum, plasma, saliva, feces or urineusing assays, including but not limited to, immunoassays, competitiveimmunoassays, mass spectrometry, e.g., liquid chromatography-tandem massspectrometry (LC/MS-MS) or tandem mass spectrometry (MS-MS). In someembodiments, the level of total or free cortisol in serum, plasma,saliva, urine or feces is determined using an immunoassay such as, butnot limited to, the ADVIA Centaur® Cortisol assay (Siemens HealthcareGlobal), ARCHITECT i2000SR cortisol (Abbott), Immulite® 2000 Cortisolassay (Siemans Healthcare Global; #L2KCO2), Vitros® ECi Cortisol assay(Ortho Clinical Diagnostics; #107 4053), and Elecsys® CortisolImmunoassay (Roche Molecular Diagnostics; #11875116160). One of ordinaryskill in the art will recognize that any method for detecting cortisollevels in a biological sample taken from a subject, e.g., human subjectcan be used.

G. Kits

The present invention provides kits. The kits comprise daily doses ofthe GRA and GC and in some cases, a biological sample collecting device.In some embodiments, the kit also includes any other component necessaryto perform the methods described herein, such as a container,instructions for drug administration, and instructions for samplecollection.

In some cases, a patient's plasma is collected by any known plasmacollection device. Some plasma collection devices useful in the presentinvention include, but are not limited to, vacutainers. The plasmacollection devices can optionally comprise additives in the device, suchas anticoagulants (EDTA, sodium citrate, heparin, oxalate), a gel withintermediate density between blood cells and blood plasma, particlescausing the blood to clot, a gel to separate blood cells from serum,thrombin and fluoride, among others.

III. Examples Example 1: Case Report of Treating a Female PatientSuffering from Secondary Adrenal Insufficiency with a Glucocorticoid anda Glucocorticoid Receptor Antagonist

The patient is a 39 year old woman who developed depression at the ageof 20 for which she was placed on various psychotropic medications. Atage 28, she developed progressive malaise, 25 pound weight gain, muscleweakness, easing bruising, hypertension and foot stress fracture. At age31, she underwent screening DEXA bone density scan because of herpersonal history of fracture and a family history of advancedosteoporosis and genetically confirmed hypophosphatasia in her mother.The DEXA bone density scan disclosed a T-score of −3.4 at the lumbarspine and −3.1 at the hip. DNA sequencing of the ALPL (alkalinephosphatase, liver/bone/kidney) gene revealed no detectabledisease-causing mutations. Further testing for secondary causes ofosteoporosis included 24-hour urinary free cortisol which was markedlyelevated at 499 mcg/day (range 10-80 mcg/day). Plasma ACTH level wasundetectable. Adrenal imaging revealed a 3-cm right adrenal mass. At age33, she underwent uncomplicated right laparoscopic adrenalactomy andhistopathology confirmed a 3.7 cm adrenal cortical adenoma. The patientunderwent a unilateral procedure, leaving one adrenal gland intact.

Post-operatively the patient was placed on hydrocortisone replacement,initially at a dose of 40 mg/day given in divided doses and graduallytapered to 30 mg/day over the following several months. One year afterher adrenalectomy, her hydrocortisone had been further tapered to 15mg/day, which remained her maintenance dose.

During the ensuing 6 years after her adrenalectomy, the patientgenerally felt unwell with symptoms of episodic nausea, headaches,lightheadedness, mood swings and generalized weakness. Quarterlymeasurement of serum cortisol and plasma ACTH levels (performed afterholding hydrocortisone for 18 hours) consistently yielded undetectablevalues for both parameters. During this 6 year period, she had onepregnancy, occurring 3 years after adrenalectomy and progressing tofull-term delivery of a healthy boy. She had two other hospitalizations(separated by 4 years) for near-syncope, malaise, nausea and vomiting(but without hypoglycemia or hypotension). Both episodes were treatedwith 48-hours of intravenous stress-doses of glucocorticoids and saline,followed by improvement of her symptoms and subsequent tapering ofglucocorticoids to a replacement dose of hydrocortisone 15 mg/day.

The failure of the HPA axis to recover six years after adrenalectomy(despite physiological steroid dosing) prompted magnetic resonanceimaging of the sella to rule out structural abnormalities of thehypothalamus, infundibulum and pituitary. This MRI was unremarkable. Atthat time, after a balanced discussion of risk and benefit, mifepristone150 mg every other day was initiated and the dose of hydrocortisone 15mg/day was continued. Over the ensuing five months, the dose ofmifepristone was gradually escalated to 300 mg every other day, then 300mg daily and finally maintained at 600 mg daily. During this time, rapidrecovery of the HPA axis was noted (initially with a rise in ACTH intothe supra-normal range 4-months after starting mifepristone, followed bya subsequent rise in cortisol levels). The dose of hydrocortisone waslowered and ultimately stopped 8 months after initiation ofmifepristone. The patient tolerated mifepristone remarkably well; withthe only side effects being amenorrhea and pruritis (she had apre-existing history of urticaria). The pruritis was tolerable andmanaged with over the counter anti-histamines. At no point duringtreatment with mifepristone did the patient develop signs or symptoms ofadrenal insufficiency. Her menses returned 3 weeks after discontinuationof mifepristone. Table 1 summarizes recovery of the HPA axis afterinitiation of mifepristone.

TABLE 1 Drug Dosing Schedule and Response Month 0 1 3 4 5 6 8 10 11 Mifedose (mg) 0 150 300 300 600 600 300 0 0 TIW TIW daily daily daily TIW HCdose (mg) 15 15 15 15 15 10 0 0 0 ACTH (pg/mL) 5 15 18 60 78 173 126 2645 Cortisol (ug/dL) <1 <1 <1 3.6 4.6 10.5 13.6 13.5 15.3 DHEA (ng/mL)<0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 0.053 “Mife” denotesmifepristone. “HC” denotes hydrocortisone. “TIW ” denotes three timesper week.

This example illustrates that a patient with second adrenalinsufficiency was successfully treated by co-administration ofhydrocortisone and mifepristone. Recovery of the patient's HPA axis wasachieved. The patient's ACTH and cortisol levels increased in responseto the drug treatment. Normal levels of ACTH and cortisol weremaintained after completion of the treatment.

The terms and expressions which have been employed herein are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding equivalents of thefeatures shown and described, or portions thereof, it being recognizedthat various modifications are possible within the scope of theinvention claimed. Moreover, any one or more features of any embodimentof the invention may be combined with any one or more other features ofany other embodiment of the invention, without departing from the scopeof the invention. All publications, patents, and patent applicationscited herein are hereby incorporated by reference in their entirety forall purposes.

What is claimed is:
 1. A method of treating secondary adrenalinsufficiency, the method comprising co-administering a therapeuticallyeffective amount of a glucocorticoid (GC) and a non-steroidalglucocorticoid receptor antagonist (GRA) to a patient in need thereof,wherein administering said non-steroidal GRA comprises administeringinitial low dose amounts of the non-steroidal GRA once per day alongwith initial high dose amounts of said GC administration for at least aweek, wherein said once-daily initial low dose amount said non-steroidalGRA is between 100 milligrams (mg) and 150 mg of the non-steroidal GRA,and wherein said initial high dose amount of said GC is between 15 and30 mg of the GC, and then continuing to administer the GC and continuingto administer the non-steroidal GRA once per day, wherein said continuedonce per day non-steroidal GRA administration is at a non-steroidal GRAdose amount that is greater than said initial GRA low dose amount, andwherein said continued GC administration is at a GC dose amount that isless than said initial GC high dose amount, effective to increase thepatient's morning plasma levels of cortisol to at least about 12 μg/dL,whereby said secondary adrenal insufficiency is treated, wherein theglucocorticoid receptor antagonist backbone is a fused azadecalin or acyclohexyl pyrimidine.
 2. The method of claim 1, wherein the patient issuspected of having secondary adrenal insufficiency after successfulsurgery for endogenous Cushing's syndrome.
 3. The method of claim 1,wherein the patient is suspected of having secondary adrenalinsufficiency after successful surgery of a pituitary ACTH-secretingtumor, an extra-adrenal cortisol secreting tumor, a unilateralhyperplastic adrenal gland associated with autonomous cortisolsecretion, an ectopic ACTH secreting non-pituitary tumor, or aunilateral adrenocortical cortisol secreting tumor.
 4. The method ofclaim 1, wherein the patient has not received glucocorticoid andglucocorticoid receptor antagonist treatment.
 5. The method of claim 4,wherein the patient has not been treated for a disorder or conditionselected from the group consisting of glaucoma, inflammatory diseases,rheumatoid arthritis, asthma and rhinitis, chronic pulmonary disease,allergies, and autoimmune diseases.
 6. The method of claim 4, whereinthe patient has not been treated to reduce a side effect ofglucocorticoid treatment.
 7. The method of claim 6, wherein the sideeffect is selected from the group consisting of weight gain, glaucoma,fluid retention, increased blood pressure, mood swings, cataracts, highblood sugar, diabetes, infection, loss of calcium from bones,osteoporosis, menstrual irregularities, fat redistribution, growthretardation, and cushingoid appearance.
 8. The method of claim 1,wherein the glucocorticoid receptor antagonist backbone is a cyclohexylpyrimidine.
 9. The method of claim 8, wherein the cyclohexyl pyrimidinehas the following formula:

wherein the dashed line is absent or a bond; X is selected from thegroup consisting of O and S; R¹ is selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionallysubstituted with from 1 to 3 R^(1a) groups; each R^(1a) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkyl OR^(1b), halogen, C₁₋₆ haloalkyl, C₁₋₆haloaloxy, OR^(1b)NR^(1b)R^(1c), C(O)R^(1b), C(O)OR^(1b), OC(O)R^(1b),C(O)NR^(1b)R^(1c), NR^(1b)C(O)R^(1c), SO₂R^(1b), SO₂NR^(1b)R^(1c),cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R^(1b) and R^(1c) areeach independently selected from the group consisting of H and C₁₋₆alkyl; R² is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkyl-OR^(1b), C₁₋₆ alkyl NR^(1b)R^(1c) and C₁₋₆ alkyleneheterocycloalkyl; R³ is selected from the group consisting of H and C₁₋₆alkyl; Ar is aryl, optionally substituted with 1-4 R⁴ groups; each R⁴ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, C₁₋₆ haloalkyl and C₁₋₆ haloalkoxy; L¹ is a bond orC₁₋₆ alkylene; and subscript n is an integer from 0 to 3, or salts andisomers thereof.
 10. The method of claim 1, wherein the glucocorticoidreceptor antagonist backbone is a fused azadecalin.
 11. The method ofclaim 10, wherein the fused azadecalin is a compound having thefollowing formula:

wherein L¹ and L² are members independently selected from a bond andunsubstituted alkylene; R¹ is a member selected from unsubstitutedalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl,—OR^(1A), NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), and —C(O)OR^(1A), whereinR^(1A) is a member selected from hydrogen, unsubstituted alkyl andunsubstituted heteroalkyl, R^(1C) and R^(1D) are members independentlyselected from unsubstituted alkyl and unsubstituted heteroalkyl, whereinR^(1C) and R^(1D) are optionally joined to form an unsubstituted ringwith the nitrogen to which they are attached, wherein said ringoptionally comprises an additional ring nitrogen; R² has the formula:

wherein R^(2G) is a member selected from hydrogen, halogen,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃; J is phenyl;t is an integer from 0 to 5; X is —S(O₂)—; and R⁵ is phenyl optionallysubstituted with 1-5 R^(5A) groups, wherein R^(5A) is a member selectedfrom hydrogen, halogen, —OR^(5A1), S(O₂)NR^(5A2)R^(5A3), —CN, andunsubstituted alkyl, wherein R^(5A1) is a member selected from hydrogenand unsubstituted alkyl, and R^(5A2) and R^(5A3) are membersindependently selected from hydrogen and unsubstituted alkyl, or saltsand isomers thereof.
 12. The method of claim 1, wherein theglucocorticoid is selected from the group consisting of hydrocortisone,prednisone, dexamethasone, a glucocorticoid analogue, a syntheticglucocorticoid analogue, and derivatives thereof.